This invention relates to atrial peptides and more particularly to a method of prolonging or enhancing the biological activity of atrial peptides.
In recent years, considerable research investigation has been made on the atrial peptides. These are polypeptide hormones which were originally extracted from the heart atrial muscle. They have been denoted by various terminology such as cardionatrin, atrial natriuretic factor (ANF), atriopeptin (AP), atriopeptigen and auriculin. Biological activity has been shown with these peptides having amino acid chain lengths from as short as about 18 amino acids to as long as over 100 amino acids. The biological activity includes diuretic, natriuretic, smooth muscle relaxing, blood pressure lowering and other such properties having an important role in the regulation of volume balance, sodium homeotasis and vascular tone.
A great number of detailed articles have been published on the structure and biological properties of various of the atrial peptides. For brief background information on the atrial peptides in general, reference can be made to the following recent publications and the references cited therein:
Sagnella and MacGregor, Nature 309, 666-667 (1984); PA0 Palluk et al., Life Sci. 36(15), 1415-1425 (1985); PA0 Needleman et al., Hypertension 7(4), 469-482 (1985); PA0 de Bold, Science 230, 767-770 (1985); and PA0 Needleman and Greenwald, N. Eng. J. Med. 314(13), 828-834 (1986).
An important group of atrial peptides of significant interest, known as Atriopeptins I, II and III (AP-I, AP-II and AP-III), are described, for example, by Currie et al. Science 223, 67-69 (1984); Geller et al., Biochem. Biophys. Res. Commun. 120(2), 333-338 (1984); and Needleman, U.S. Pat. No. 4,496,544. These peptides in the oxidized (cyclized) form have the following amino acid sequences: ##STR1##
Extensions of AP-III have also been described. Thus, the 28 amino acid peptide ser-leu-arg-arg-AP-III (SLRR-AP-III), also known as Cardionatrin I, is disclosed in European Patent Application No. 116,784, published Aug. 29, 1984. The human analog of the 28 amino acid Cardionatrin I having a met.sup.12 replacement for ile.sup.12 is described by Kangawa and Matsuo, Biochem. Biophys. Res. Commun. 118(1), 131-139 (1984).
The 26 amino acid peptide arg-arg-AP-III, also known as atrial natriuretic factor or ANF (8-33), is disclosed as a fragment of a larger 33 amino acid peptide by Seidah et al., Proc. Nat. Acad. Sci. USA 81, 2640-44 (1984).
The 25 amino acid analog of AP-III having an arg extension at the amino acid terminus, also known as auriculin, is described by Yamanaka et al., Nature 309, 719-22 (1984).
The relationship of the foregoing small peptides to a common precursor is illustrated by Sagnella and MacGregor, Nature 309, 666-667 (1984).
As reported in the literature, these small atrial peptides have been shown to have potent diuretic activity upon intravenous administration. For example, such effects have been shown in the dog at 10-30 .mu.g/kg i.v. and at 100 .mu.g i.v. bolus in humans.
Despite the useful biological activity of the atrial peptides, it has been reported that they have a relatively short half-life. See, for example, Burnett et al., Am. J. Physiol. 247, F863-F866 (1984); Luft et al., J. Pharmacol. Exp. Ther. 236(2), 416-418 (1986); and Yandle et al., Life Sci. 38, 1827-1833 (1986). It has also been suggested that proteolytic degradation causes relatively rapid loss of the atrial peptide bioactivity. For example, inactivation of atrial peptide by renal kallikrein was described by Briggs et al., Am. J. Physiol. 247 (3, Pt. 2), F480-F484 (1984); and Thibault et al., Can. J. Physiol. Pharmacol. 62(6), 645-649 (1984). Proteolytic degradation of atrial peptide by kidney and liver homogenates has been described by Tang et al., Regul. Pept. 9(1-2), 53-9(1984).
Harris et al., Peptides (Fayettsville, N.Y.) 6(3), 393-396 (1985), reported that AP-II is converted to AP-I by a bovine atrial enzyme, namely, atrial dipeptidyl carboxhydrolase, which is a metalloenzyme. This does not, however, constitute inactivation but conversion from one active form of the atrial peptide to another during processing.
Methods of prolonging or enhancing the bioactivity of atrial peptides thus would provide significant advantages in the use of these peptides. Several peptidase inhibitors which have been suggested heretofore as useful in preventing enzymic degradation of the atrial peptides are bestatin, an aminopeptidase inhibitor; SQ 20881, a carboxypeptidase inhibitor; and aprotinin, an inhibitor of serine protease. See Tang et al., supra, and Thibault et al., supra.